PROJECT SUMMARY/ ABSTRACT Essential tremor (ET) is the most common movement disorder with 4% of the population over age of 40. In addition to the high prevalence, ET is also a progressive disorder and tremor becomes more severe over time, leading to disability. Therapeutic options for ET are far from satisfactory, and there is no existing therapy can slow down the disease progression to prevent disability, in part due to an unclear understanding of the disease mechanism. Recent advances of ET neuropathology and animal models of tremor indicate that cerebellar excitatory synapses play a role in tremor. Moreover, a recent genome-wide association study (GWAS) has identified the association of excitatory amino acid type 2 (EAAT2) in ET, providing clues of astrocytic contribution to excitatory synapses in ET. However, the detailed mechanism how cerebellar excitatory synapses and astrocytes could influence tremor still remain obscure, which will be important knowledge to bridge the prior discoveries into therapeutic development. In this proposal, we will test the hypothesis that excessive cerebellar excitatory synaptic transmission, modulated by astrocytic EAAT, contribute to PC degeneration and progressive tremor, using both animal models and postmortem human ET brains. We will determine whether the speed of tremor progression or PC degenerative changes can be altered by either long-term over- excitation of cerebellar excitatory synapses (Aim 1) or the manipulation of cerebellar EAAT2 levels (Aim 2) in a novel mouse model of tremor. We will also test whether astrocytic pathology and related PC pathology could be observed in genuine ET and correlate with tremor severity by studying structural alterations in postmortem human ET brains (Aim 3). These data will advance our understanding of cerebellar excitatory synapses in tremor and will provide scientific basis to develop mechanism-based therapies for ET.